Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity.

CONTEXT: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. OBJECTIVE: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. DESIGN: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. RESULTS: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. CONCLUSION: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.

Endoscopic treatment with transmural drainage and necrosectomy for walled-off necrosis provides favourable long-term outcomes on pancreatic function.

BACKGROUND AND AIMS: Several studies have shown improved short-term outcome with endoscopic transmural drainage and necrosectomy for the treatment of walled-off pancreatic necrosis. However, knowledge on the long-term prognosis after such treatment is limited. The aim of present study was to evaluate long-term outcomes in patients endoscopically treated with transmural drainage and necrosectomy. METHODS: We retrospectively follow up 125 patients with walled-off pancreatic necrosis treated with endoscopic transmural drainage and necrosectomy in 2010-2017. All patients received plastic pigtail stents and nasocystic catheter. Additional external drainage was performed in 41 patients. Main outcomes were survival, pancreatic function, development of co-morbidities, ability to work and social status. RESULTS: During a median follow-up of 4.3 years, nine (7%) patients died. Seven deaths were unrelated to pancreatic disease, and two patients died of pancreatic cancer. Twenty-two (18%) patients developed exocrine pancreatic insufficiency. Thirty-six (32%) previous non-diabetics developed endocrine insufficiency. Endoscopic necrosectomy during admission (odds ratio (OR) = 1.28, 95% confidence interval (CI) 1.05-1.56; p = 0.015) and therapy on the main pancreatic duct (OR = 8.08, 95% CI 2.43-26.9; p < 0.001) during follow-up predicted development of exocrine insufficiency. Severity on computed tomography predicted endocrine insufficiency (OR = 1.61, 95% CI 1.24-2.09; p < 0.001). Most patients regained their working capacity and preserved their marital status. CONCLUSIONS: This study provides robust data on the long-term outcome of patients with walled-off pancreatic necrosis treated with endoscopic transmural drainage and necrosectomy. The favourable outcomes on survival, pancreatic function and social status support current recommendations of endoscopic transmural drainage and necrosectomy being the treatment of choice for walled-off pancreatic necrosis.

Utility of Direct Pancreatic Function Testing in Children.

OBJECTIVES: Exocrine pancreatic insufficiency (EPI) can have a significant impact on a child's growth and nutrition. Our aim was to evaluate the utility of direct endoscopic pancreatic function testing (ePFT) in pediatrics. METHODS: A single-center retrospective chart review was performed of children who underwent ePFT from December 2007 through February 2015. Endoscopic pancreatic function testings were performed by 1 of 2 methods: (1) intravenous cholecystokinin, followed by the collection of a single duodenal aspirate at 10 minutes, or (2) intravenous cholecystokinin or secretin, followed by the collection of 3 duodenal aspirates at a 5, 10, and 15 minutes. Samples were tested for pH and enzyme activities. RESULTS: A total of 508 ePFTs were performed (481 single-sample tests, 27 multiple-sample tests). Based on the multiple-sample group, enzyme levels for chymotrypsin, amylase, and lipase peaked at 5 minutes, followed by a decrease in activity over time. Exocrine pancreatic sufficiency was identified in 373 (73.4%) and EPI in 93 (18.3%). Exocrine pancreatic sufficiency analysis found all pancreatic enzyme activities significantly increase with age: trypsin, chymotrypsin, amylase, and lipase, (P < 0.05). CONCLUSIONS: Endoscopic pancreatic function testing can be used in the evaluation of EPI in children. Normative data suggest that pancreatic enzyme activities mature with age.

Quantification of pancreatic function using a clinically feasible short endoscopic secretin test.

OBJECTIVES: Clinical and morphological criteria are not precise enough to diagnose early chronic pancreatitis (CP). We investigated if short endoscopic pancreas function testing as a part of routine upper endoscopy could improve clinical diagnostics. METHODS: Patients with suspected CP underwent modified secretin-stimulated upper endoscopy (short endoscopic secretin test, or EST). Duodenal juice was collected during 15 minutes starting 30 minutes after stimulation. A modified scoring system for CP after Layer with bicarbonate and fecal elastase 1 (FE1) was used. We tested with receiver operating characteristic curves the diagnostic accuracy of bicarbonate and FE1 and with analysis of variance how precise the 2 parameters can discriminate the groups. RESULTS: Fifty-two patients aged 19 to 67 years and 25 healthy controls aged 19 to 64 years were included. Twenty-four patients fulfilled the modified Layer Score for CP or non-CP. The overall accuracy of the EST versus FE1 test was 85%/71%, with positive and negative predictive values of 100%/79% and 80%/69%, respectively. CONCLUSIONS: Short EST is rapid and easy to perform and can be incorporated in daily routines. We demonstrate that EST is superior to FE1 in the assessment of pancreatic insufficiency and may prove to be useful in diagnosing early or mild CP.

An automated analyzer provides clinically concordant results to manual back titration for quantitation of bicarbonate in pancreatic juice.

OBJECTIVES: Secretin pancreatic function tests play an important role in the diagnosis of chronic pancreatitis. Back titration is the standard method for measurement of bicarbonate in pancreatic juice but is time consuming and manually performed. Use of an autoanalyzer for this purpose is not validated. METHODS: Bicarbonate concentrations in secretin-stimulated pancreatic juice specimens were quantitated by manual back titration, a clinical chemistry autoanalyzer (automated bicarbonate, Roche Cobas c501, Roche Diagnostics, Indianapolis, Ind), and a blood gas analyzer (calculated bicarbonate, GEM 3000, Instrumentation Laboratories, Bedford, Mass). Kappa statistic analysis, Bland-Altman analysis, and Lin concordance correlation coefficients were calculated. RESULTS: Ninety specimens from 31 subjects were included. Using a bicarbonate concentration of 80 mEq/L as a cutoff value, there was poor agreement between back titration and calculated bicarbonate (κ = 0.188); however, only 1 specimen showed discrepancy between back titration and automated bicarbonate (κ = 0.977). The limit of agreement between the back titration and automated bicarbonate was -9.0 to + 8.3 mEq/L. The Lin concordance correlation coefficient between the 2 methods was 0.931 (P < 0.001). CONCLUSIONS: There is strong concordance between manual back titration and chemistry autoanalyzer methods for measurement of bicarbonate concentrations in pancreatic juice. Autoanalyzers may replace back titration for this purpose. Blood gas analyzers are unsuitable.

Within-subject variability of measures of beta cell function derived from a 2 h OGTT: implications for research studies.

AIMS/HYPOTHESIS: Knowledge of the within-subject variability of a parameter is required to properly design and calculate sample sizes for longitudinal studies. We sought to determine the day-to-day variability of measures of beta cell function derived from an OGTT. METHODS: Thirty-seven adults (13 with normal glucose tolerance, ten with impaired glucose tolerance, 14 with type 2 diabetes) underwent a standard 2 h 75 g OGTT on two separate days (median time between tests, 7 days; range, 5-14). From these data, the reproducibility of several indices of beta cell function were determined: insulinogenic index (DeltaI(0-30)/DeltaG(0-30)), early C-peptide response (DeltaCP(0-30)/DeltaG(0-30)), incremental AUC insulin to glucose response (incAUC(ins)/incAUC(glu)), integrated insulin secretion response from 0 to 120 min (IS/Glu(0-120)) and indices of beta cell function derived from a mathematical model. RESULTS: Within-subject variability for DeltaI(0-30)/DeltaG(0-30) (CV 57.1%) was higher than DeltaCP(0-30)/DeltaG(0-30) (CV 34.7%). Measures integrated over the full 120 min of the OGTT, incAUC(ins)/incAUC(glu) (CV 24.9%) and IS/Glu(0-120) (CV 17.4%), demonstrated less variability. The mathematical model-derived measures of beta cell glucose sensitivity (CV 20.3%) and potentiation (CV 33.0%) showed moderate variability. The impact of the different measures' variability on sample size (30% change from baseline) is demonstrated by calculated sample sizes of 89 for DeltaI(0-30)/DeltaG(0-30), 37 for DeltaCP(0-30)/DeltaG(0-30), 21 for incAUC(ins)/incAUC(glu) and 11 for IS/Glu(0-120). CONCLUSIONS/INTERPRETATION: Some OGTT-derived indices of beta cell function, in particular the insulinogenic index, demonstrate high within-subject variability. Integrated measures that utilise multiple time points and measures that use C-peptide show less variability and may lead to a reduced sample size requirement.

Fecal elastase-1 is superior to fecal chymotrypsin in the assessment of pancreatic involvement in cystic fibrosis.

OBJECTIVE: Exocrine pancreatic function in patients with cystic fibrosis (CF) can be evaluated by direct and indirect tests. In pediatric patients, indirect tests are preferred because of their less invasive character, especially in CF patients with respiratory disease. Fecal tests are noninvasive and have been shown to have a high sensitivity and specificity. However, there is no comparative study in CF patients. Therefore, the aim of the present study was to compare the sensitivity and the specificity of the fecal elastase-1 (E1) test with the fecal chymotrypsin (ChT) test in a large cohort of CF patients and healthy subjects (HS). DESIGN: One hundred twenty-three CF patients and 105 HS were evaluated. In all subjects, E1 concentration and ChT activity were measured. In the CF group, fecal fat excretion was also determined. The sensitivity and specificity of the fecal E1 test and ChT test were compared. RESULTS: With a cutoff level of 3 U/g, ChT specificity in HS was similar to that of E1, but E1 sensitivity in CF patients was significantly higher (90.2% vs 81.3%). With a cutoff level of 6 U/g, ChT and E1 sensitivity in CF patients was identical, but E1 specificity in HS was again significantly higher (98.1% vs 90.5%). In all CF patients with severe steatorrhea (>15 g/d), E1 concentrations were abnormal and ChT activity was lower than 3 U/g. In contrast, in pancreatic-sufficient patients and patients with mild steatorrhea (< or =15 g/d), the E1 sensitivity was significantly higher compared with ChT (69.2% vs 41.0%). CONCLUSIONS: The fecal E1 test is superior to fecal ChT determination in the assessment of CF pancreatic involvement in pancreatic-sufficient patients and those patients with mild steatorrhea.

Duct-parenchymal ratio predicts exocrine pancreatic function after pancreatoduodenectomy and distal pancreatectomy.

BACKGROUND: The postoperative exocrine pancreatic function was compared between pancreatoduodenectomy and distal pancreatectomy, and we studied the relationship between the preoperative morphology of the pancreas expected to remain and pancreatic function after surgery. PATIENTS AND METHODS: In 27 patients who underwent pylorus-preserving pancreatoduodenectomy (PPPD group) and 12 who underwent distal pancreatectomy (DP group), the exocrine pancreatic function was assessed using the BT-PABA excretion test before surgery and short term after surgery (< or =2 months). Preoperative morphology of the pancreas at a presumed line of transection was also investigated on computed tomography. RESULTS: The mean urinary PABA excretion rate in the PPPD group decreased from 68.3% to 53.7% (P = 0.0029), whereas that in the DP group showed no significant change (70.7% versus 72.7%). The mean size of the main pancreatic duct at the presumed transection line in the PPPD group was significantly greater than that in the DP group (6.5 mm versus 2.6 mm, P = 0.0002). The mean parenchymal thickness of the pancreatic gland at the presumed transection line in the PPPD group was significantly smaller than that in the DP group (16.1 mm versus 18.6 mm, P = 0.04). The mean ratio of the pancreatic duct caliber to parenchymal thickness (duct-parenchymal ratio) in the PPPD group was significantly higher than that in the DP group (0.43 versus 0.14, P = 0.0004). There was a significant negative correlation between the postoperative PABA excretion rate and the duct-parenchymal ratio (P = 0.0057). CONCLUSIONS: The postoperative exocrine pancreatic function after PPPD and DP was significantly influenced by the morphology of the pancreas at the presumed transection line. It is important to evaluate the preoperative morphology of the presumably remaining pancreas, especially duct-parenchymal ratio, to predict the exocrine pancreatic function short term after pancreatectomy.

Intraductal secretin test is as useful as duodenal secretin test in assessing exocrine pancreatic function.

We assessed the clinical usefulness of the intraductal secretin test in order to ascertain whether it can substitute for the conventional duodenal secretin test. Duodenal juice was obtained with a triple-lumen tube and pure pancreatic juice was obtained by retrograde cannulation of the main pancreatic duct using a duodenofiberscope. Pancreatic secretion was stimulated by a bolus intravenous injection of secretin (100 units). The two tests showed comparable interindividual coefficients of variation, significantly good correlations, and comparable diagnostic efficiencies. The intraductal secretin test showed no less reproducibility than that of the duodenal secretin test as reported in the literature. In the intraductal secretin test, secretory volume, peak flow rate, bicarbonate output, and lipase output yielded the best diagnostic efficiency, followed by amylase output and maximal bicarbonate concentration. In the intraductal secretin test, a 10-min collection provided as much information as a 20-min collection. We conclude, therefore, that the 10-min intraductal secretin test is as useful as the conventional duodenal secretin test in assessing exocrine pancreatic function and that the most discriminatory parameters are secretory volume, bicarbonate output, and amylase (or lipase) output.

Pancreatic insufficiency in celiac disease is not dependent on nutritional status.

To determine the relationship between pancreatic secretory capacity and nutritional status in celiac patients, we studied 52 patients with celiac disease (24 males, 28 females; age range 6-36 months) and 30 healthy control subjects (14 males, 16 females; age range 6-42 months). A secretin-cerulein test was performed on all patients, and levels of serum albumin and plasma fibronectin were assayed. In addition, weight/height ratios were calculated in the celiacs, who were then divided into three groups on this basis, as follows: celiacs with weight/height ratio < or = 3rd percentile; those with weight/height ratio between the 4th and 10th percentiles; and those with weight/height ratio > 10th percentile. There was no significant difference in the duodenal output of chymotrypsin, phospholipase and lipase between these groups. When the total celiac group was compared to control subjects, only lipase levels were significantly lower (P < 0.009). However, subnormal values in one or more pancreatic enzymes were observed in 15/52 celiacs (29%). A residual enzyme activity < 10% of normal secretory capacity, was also found in 4/52 patients. There was no correlation between the output of the various pancreatic enzymes and levels of albumin, fibronectin, and weight/height ratios in the patients. Furthermore, there was no difference in weight/height ratios and levels of albumin and fibronectin between the celiac subjects with pancreatic deficiency and those with normal pancreatic function. We conclude that a mild/moderate pancreatic insufficiency is quite frequent in celiacs, but that it may be completely independent of nutritional status; further studies are therefore required to shed light on its pathogenesis.

[Changes in the pancreatic and respiratory functions in cystic fibrosis. The influence of the time of the evolution of the disease]. / Alteración de la función pancreática y respiratoria en la fibrosis quística. Influencia del tiempo de evolución de la enfermedad.

BACKGROUND: Cystic fibrosis is the most frequent congenital disease in Caucasian and is transmitted by recessive autosomic inheritance. It is characterized by affection of different glands of exocrine secretion, particularly the pancreas and the lung. The aim of this study was to analyze the degree of alteration of pulmonary and pancreatic exocrine function in a group of patients with cystic fibrosis in relation to the time of disease evolution. METHODS: Twenty-one patients between 9 and 31 years of age were studied; 11 with an evolution of lower than or equal to 158 months and 10 with an evolution of higher than 158 months (median of the total patients). To study pancreatic exocrine function the BT-PABA test immunoreactive serum trypsin test were used. To evaluate respiratory function FEV1, FVC, FEV1/FVC ratio and PaO2 were used. RESULTS: The results obtained demonstrated that in the group with a lower time of evolution the diagnosis had been carried out at earlier ages (17 +/- 17 months versus 84 +/- 60 months; p = 0.002) and presented a significantly more altered pancreatic exocrine function (BT-PABA: 13 +/- 12% versus 35 +/- 23%; p = 0.013). However, respiratory function was altered in the group with longer time of evolution (FEV1: 68 +/- 20% versus 36 +/- 23%; p = 0.003; FVC: 74 +/- 9 versus 52 +/- 25%; p = 0.013; FEV1/FEV: 77 +/- 19 versus 50 +/- 9%; p < 0.001; PaO2: 84 +/- 16 versus 58 +/- 11%; p < 0.001). CONCLUSIONS: Pancreatic exocrine function is most intensely affected in patients diagnosed with cystic fibrosis at earlier and with shorter times of evolution while patients who have the longest time of evolution and who were diagnosed later in life presented greater changes in respiratory function.